My career objectives over the next five years are (1) to recruit and mentor young investigators interested in translational HIV research, (2) to further define the pathogenesis of drug-resistant HIV, and (3) to established a well-characterized cohort of HIV-seropositive individuals who in the absence of therapy are able to durably maintain undetectable plasma HIV RNA levels (the so-called "elite" controllers). These goals will be pursued in the context of a multi-disciplinary research program aimed at translating basic research findings into the clinic while also collecting biologic specimens from well-characterized cohorts for focused laboratory-based research. Specifically, I will direct a study aimed at testing the hypothesis that drug-resistance mutations attenuate the pathogenicity of HIV. I will also direct two prospective pilot studies, one aimed at determining if antiretroviral therapy can be used intermittently to increase CD4+ T cell counts in patients with drug-resistant viremia and one aimed at preventing the establishment of drug-resistant virus in the latent reservoir. Finally, I will expand our model to include "elite" controllers, and will direct a series of multi-disciplinary studies aimed at understanding the mechanisms of virus control in these individuals. I currently devote approximately 50% of total effort to clinical care and administrative/teaching responsibilities. With the support of a K24 award, I will decrease my clinical and teaching commitments, thus allowing me to focus on patient-oriented research and mentoring. Also, I will be able reduce my commitment as a co-investigator on grants that are not directly related to the aims outlined in this proposal. Public health implications: A significant and possibly growing proportion of HIV-infected patients harbor drug-resistant HIV. The studies outlined here will investigate novel approaches to prevent and manage HIV drug-resistance. Also, we believe that insights regarding the mechanisms operative in elite controllers will prove to be highly informative for future efforts aimed at preventing HIV infection and eradicating virus in those already infected.